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Extracorporeal Circulation Induces
a Marked Increase on Plasma
Endothelin Levels

Bitzikas, Grigorios1; Didilis, Vassilios1;
Bakogeorgou, Efstathia2; Hatzoglou, Anastassia2;
Tripsianis, Grigorios1; Castanas, Elias2;
Bougioukas, Georgios1

1 Department of Thoracic and Cardiac Surgery,
University of Thrace, Alexandroupolis, Greece
2 Laboratory of Experimental Endocrinology, University of Crete,
School of Medicine, Heraklion, GR-71110, Greece

SUMMARY
Background: Endothelin (ET) is an endothelium-derived vasoconstrictor. Increased release of ET occurs in different groups of patients undergoing various heart procedures.
Objectives: To determine the variation of circulating ET plasma levels in patients undergoing elective cardiac surgery, with extracorporeal circulation (CPB).
Material and methods: We measured plasma ET levels in 12 patients (mean age 59,9 ± 15,6 yrs) undergoing heart surgery with CPB. Nine patients underwent coronary artery bypass operation, 1 patient resection of a left atrial myxoma and 2 patients underwent valve replacement. Mean total CPB time was 95±26,6 (42-120) min and mean aorta cross-clamp time was 49,9 ± 15,04 (18-67) min.
ET levels were detected in 9 perioperative phases (pre-, during and post CPB) in a total period of 48hrs. ET plasma concentrations were assayed by the use of an Endo-thelin radioimmunoassay kit.
The statistical analysis of mean ET values for every phase was performed using the "non parametric Wilcoxon Matched-Pairs signed Ranks test".
Results: Compared to the preoperative values a statistically significant increase on circulating ET was observed 5 min after weaning from CPB. At that phase, ET values peaked in all patients except one. That increase remained significant two hours after admission in ICU. In addition, CPB induced an increase on mean ET value of 52,1%. That change was not related to the total CPB time or aorta cross-clamp time. On the 1st postoperative day ET levels returned to the preoperative values.
All patients except one had an uneventful postoperative course. One patient presented with a postoperative low cardiac output syndrome, which was successfully treated.
Conclusions: Extracorporeal circulation induced a marked increase on plasma ET levels which peaked just after the CPB weaning. After twenty-four hours mean ET value returned to the preoperative level.

Figure 1

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OBJECTIVES
   The aim of this study is to determine the variation of circulating endothelin (ET) plasma levels in patients undergoing elective cardiac surgery, using extracorporeal cir-culation (CPB).

BACKGROUND
   Endothelin is a potent vasoconstrictor produced by endothelial cells, which is thought to provoke both systemic and pulmonary hypertension and might be involved in the pathogenesis of cardiac failure, renal failure and bronchial asthma. There are three iso-forms of ET (ET-1, ET-2 and ET-3).

   Increased release of ET occurs in different groups of patients undergoing various heart procedures, but the time course and the physiologic consequences of ET release still remain under investigation.

MATERIAL AND METHODS
   We measured plasma ET levels in 12 patients (10 males and two females) undergoing heart surgery with CPB. The mean age of patients was 59,9 ± 15,6 yrs (range: 28-74 yrs). Nine patients underwent coronary artery bypass grafting, one patient underwent resection of a left atrial myxoma and two patients underwent valve replacement (one patient aortic valve replacement and the other mitral valve replacement).

   Eight patients had a history of previous myocardial infarction and three patients pre-sented with unstable angina. The LVEF ranged between 0.40 - 0.62. All patients had normal renal function preoperatively, as this was proved by the biochemical markers (blood urea, creatinine and creatinine clearance).

   Mean total CPB time was 95±26,6 (42-120) min and mean aorta cross-clamp time was 49,9 ± 15,04 (18-67) min. Antegrade cold crystalloid cardioplegia was used in all patients. The cardiopulmonary bypass was performed under moderate systemic hypo-thermia (32º C - rectal).

    ET levels were measured in 9 perioperative phases (pre-, during and post CPB) in a total period of 48 hrs. In more details, thirty minutes before the arrival at the operating theater (phase A), 5 min after induction of anesthesia (phase B), 5 min after induction of CPB (phase C), 30 min after induction of CPB (phase D), 5 min before starting CPB weaning (phase E), 5 min after CPB weaning (phase F), 2 hours after the end of the operation - during ICU stay (phase G), in the morning of the pod#1 (phase H) and finally in the morning of the pod#2 (phase I).

   Total ET plasma concentrations were assayed by the use of an Endothelin radioimmu-noassay kit (Nicols diagnostics, San Juan Capistrano, CA), after plasma extraction by the use of C18 columns.

   Statistical analysis: The statistical analysis was performed with the use of statistical package SPSS 10.0. ET values for the nine different phases were expressed as mean ± SD. Freedman one way ANOVA was used to access the differences between ET values at the nine study phases. Post hoc analysis was performed using the "non parametric Wilcoxon Matched-Pairs signed Ranks test" with a Bonfferoni correction. Simple lin-ear regression analysis was used to determine the relationship between two continuous variables. A p value < 0,05 was considered as significant.

RESULTS
   Table 1 shows the variation of ET values in all patients at the nine study phases. Table 2 presents the mean ET value ± SD and the intermediate for every phase. The variation of mean ET values plus the 95% confidence interval is shown in Figure 1.

   Compared to the preoperative values a statistically significant (p < 0,0014) increase on mean ET value was observed 5 min after weaning from CPB (phase F). At that phase, ET values peaked in all patients except one. Two hours after the end of the operation and during ICU stay (phase G) a decrease of mean ET value was observed, but the dif-ference remained statistically significant (p < 0,0014). On the 1st postoperative day ET levels returned to the preoperative values (phase H).

   In addition, CPB (phase C, D, E, F) induced an increase on mean ET value of 52,1%. That change was not related to the total CPB time or aorta cross-clamp time.

   All patients except one had an uneventful postoperative course. One patient presented with a postoperative low cardiac output syndrome (LCOS), which was successfully treated. This patient had the peak value of ET during ICU stay.

   The Biochemical markers of renal function remained within normal limits in all patients postoperatively.

DISCUSSION
   High production and release of ET during open heart procedures is caused by damage to vascular endothelium and is related to myocardial ischemia - reperfusion syndrome.

    According to the literature ET release occurs in various groups of patients who underwent heart procedures with CPB (patients with coronary artery disease, with pulmo-nary hypertension, rheumatic valvular disease, congenital heart disease). Both the time course of ET release and the homogeneity of ET release among patients who undergo a heart procedure with CPB, still remain unclear.

    The results of this study show that induction of CPB acts as a stimulus for ET release since we observed a statistically significant increase of ET levels five minutes after induction of CPB and this is probably related to changes in arterial blood pressure. ET levels peaked during reperfusion (five min. after CPB weaning ) in all patients except one. The later patient presented with a postoperative low cardiac output syndrome and ET levels peaked during ICU stay probably due to residual cardiac ischemia. At phase F mean ET value was doubled in comparison to the preoperative one (24,04 ± 7,81 pg./ml to 12,02 ± 2,92 pg./ml).

    In the literature, most studies conclude that peak ET levels are observed 3-6 hours after the end of the operation. In the study of Tonz and colleagues maximum ET levels were observed just after CPB weaning in patients who underwent a CABG operation under nomothermia (370 C) and during ICU stay in patients who underwent a CABG operation under systemic hypothermia (280 C). From our study becomes obvious that the variation of ET levels under moderate systemic hypothermia (32º C) is similar to that under normothermia.

   ET release is a transient phenomenon as on the pod#1 ET levels returned to the preoperative values. With the exception of the patient who was complicated by LCOS all other patients had an uneventful postoperative course. ET release didn't have any consequence on renal function since that remained postoperatively within normal limits in all patients.

CONCLUSION
   Extracorporeal circulation induced a marked increase on plasma ET levels which peaked just after the CPB weaning. After twenty-four hours mean ET value returned to the preoperative level. The clinical relevance of the increase of ET levels still remains to be detected.

 

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
fgaro@fac.org.ar
fgaro@satlink.com
rbretal@fac.org.ar
rbretal@netverk.com.ar
apacher@fac.org.ar
apacher@satlink.com

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